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By Howell Sasser, PhD, and Thomas Barringer, MD
Lowering low-density lipoprotein cholesterol (LDL-C) has become the cornerstone in reducing the risk of coronary heart disease (CHD). The most popular drugs used for this purpose include statins, niacin preparations, and fibrates. All of these drugs have certain drawbacks: Most require a prescription and are generally expensive; there is a small risk of muscle or liver toxicity, especially with treatment with combinations of drugs; and the list of drug interactions is a growing challenge. Also, for various reasons, more than half of those patients prescribed these medications discontinue them within two years.1 Thus, for patients who cannot or will not use these prescription medications, or who need additional cholesterol lowering, phytochemical alternative therapies may play an important role.
Policosanol is one of several "natural" products that have been studied as potential lipid-lowering agents. In studies conducted almost exclusively by researchers working for the Cuban company Dalmer Laboratory, where the compound was first developed, policosanol has been shown to lower total cholesterol (TC) by 15% to 25% and low-density lipoprotein cholesterol (LDL-C) by 20% to 30%, and to raise high-density lipoprotein cholesterol (HDL-C) by 5% to 15%.2 It also has demonstrated effects on other physiological variables generally assumed to be protective in atherothrombotic disease states, such as platelet aggregation, LDL peroxidation, and smooth muscle cell proliferation.3 Other clinical effects that have been reported include blood pressure lowering and improvement in claudication symptoms in patients with peripheral vascular disease.4
Policosanol has been in common use in Cuba since 1991 and currently is available in the United States without a prescription from various sources including health food stores and Internet web sites. It is isolated and purified from sugar cane wax, and composed of a natural mixture of higher aliphatic primary alcohols, of which 1-octacosanol is the major constituent. Notably, the proportion of each alcohol is highly reproducible from batch to batch and stable under storage conditions. A similar compound, produced from beeswax, is widely sold in health food stores. However, all of the published clinical literature to date refers to the sugar cane wax-derived product.
Pharmacology and Mechanism of Action
Policosanol is orally administered, reaching peak levels from 30 to 120 minutes after ingestion in different animal species and humans. After absorption there is a liver first-pass effect. Radioactivity studies reveal predominant distribution into the liver, with much smaller uptake noted in the heart, aorta, fat, and plasma. Excretion is primarily fecal.2
The precise mechanism of action is uncertain. Evidence from in vitro studies suggests that policosanol may inhibit hepatic cholesterol synthesis at a step before mevalonate generation.5 There is a decrease in cellular expression of hydroxy-methylglutaryl-coenzymeA (HMG-CoA) reductase, but no direct inhibition of this enzyme.6 A study in cultured human fibroblasts showed that LDL binding, uptake, and degradation were enhanced at concentrations that did not significantly decrease cholesterol synthesis.5 Because the overall absorption of policosanol is low, but its effects are substantial, an intra-intestinal lipid-lowering effect has not been excluded. It also has been suggested that some of the secondary metabolites, such as the very long chain fatty acids, could play a significant role in the hepatic cholesterol metabolism changes induced by policosanol.7
Virtually all of the published medical literature on policosanol has been authored by researchers affiliated with the developer of the product in Cuba. A total of about 60 studies have included approximately 3,000 subjects. To date, there are no published data on Caucasian, African-American, or other non-Hispanic populations.
At policosanol doses from 5 to 20 mg/d, it has been demonstrated in hypercholesterolemic patients that there is a dose-dependent reduction in TC and LDL-C. At 5 mg/d, mean reduction in LDL-C has ranged from 11.3% to 23.7%, and 10 mg/d has induced mean reductions of LDL-C from 21.2% to 27.5%.8 Studies with 20 mg/d have demonstrated mean reductions of LDL-C of around 30%, with one study revealing no further reduction at 40 mg/d.9,10 Long-term maintenance of these lipid effects has been demonstrated in several studies with follow-up from one to five years.11
Generally, only modest (5-15%)—but desirable—increases in HDL cholesterol have been noted. However, this still yields dose-dependent reductions in the ratio of TC to HDL-C, and the ratio of LDL-C to HDL-C. A dose of 20 mg/d produces reductions of 20% to 25% for TC/HDL-C and 25% to 30% for LDL-C/HDL-C.8 Only minimal reductions in triglycerides have been observed. No studies have evaluated non-lipid biochemical markers of CHD risk, such as C-reactive protein, apoB, or total LDL particle concentration as endpoints.
Comparisons with Other Lipid-Lowering Agents. Published clinical studies have included short- and long-term, placebo-controlled and comparative studies vs. statins (lovastatin, pravastatin, and simvastatin), fibrates (bezafibrate and gemfibrozil), acipimox, and probucol.
Policosanol administered at 10 mg/d has demonstrated similar lipid-lowering efficacy to lovastatin administered at 20 mg/d.12 Lovastatin was slightly more effective in lowering TC, but policosanol was slightly more effective in increasing HDL-C. In addition, policosanol did not result in the mildly elevated transaminases and creatine phosphokinase values noted in the lovastatin group, and clinical adverse experiences were more frequent in the lovastatin-treated patients. Similar results have been obtained in comparative studies with other statins, specifically simvastatin and pravastatin.13,14
A few studies have compared policosanol with the fibrates, specifically gemfibrozil and bezafibrate. Unfortunately, most of these trials have been published only in Spanish, or exist as "data on file" in the manufacturer’s laboratory. In summary, they apparently demonstrate greater reductions with policosanol than with fibrate therapy in TC, LDL-C, apoB, and the ratios of TC/HDL-C and LDL-C/HDL-C. There were comparable increases in HDL-C, but greater reductions in triglycerides with the fibrates.
One study of combined therapy with policosanol and bezafibrate revealed that the combination was well tolerated, while policosanol augmented the HDL-C-raising and LDL-C-lowering effects of fibrate monotherapy.15
Trials in Specific Populations. The cholesterol-lowering efficacy of policosanol is similar among men and women. Maximal effects on LDL-C are observed after 6-8 weeks of treatment. Interestingly, the increase in HDL-C seems to develop much more slowly than the reduction in LDL-C.11
Two trials have demonstrated similar lipid-lowering effects of policosanol among hypercholesterolemic patients with and without Type 2 diabetes mellitus.16,17 In addition, there was no apparent impairment of glycemic control as assessed through effects on glucose and HbA1c values. However, no studies have evaluated the effect of policosanol on more sensitive indicators of impaired glucose tolerance, such as measurements of insulin resistance.
Two trials in hypercholesterolemic patients with hypertension not only resulted in favorable lipid changes, but also after six and 12 months of therapy showed a significant reduction in systolic blood pressure.4,18 Other studies have seen no impact on blood pressure. Therefore, this potential benefit has not yet been settled.
Multiple studies of policosanol in elderly populations have demonstrated efficacy, safety, and tolerability similar to that observed in younger populations.18,19 Several studies have specifically included high-risk coronary artery disease patients with the same outcomes as already noted. One study in patients with concomitant liver function test abnormalities revealed no further deterioration in hepatic function; another study in patients with nephrotic syndrome did not reveal an impact of policosanol on renal function parameters.20,21
Interactions, Safety, and Tolerability
Formal drug interaction studies in humans have not been published. However, data from long-term studies in humans have revealed no clinically apparent problems resulting from the concomitant administration of policosanol with the following drugs and drug classes: calcium antagonists, angiotensin-converting enzyme inhibitors, beta blockers, diuretics, nitrates, nonsteroidal anti-inflammatory drugs, anxiolytics, antidepressants, neuroleptics, oral hypoglycemic drugs, digoxin, thyroid hormones, and anti-ulcer drugs.22
According to the Cuban manufacturer’s product monograph, single oral doses of 1,000 mg administered to healthy volunteers were tolerated without adverse effects. In most of the published short- and long-term studies, adverse effects and tolerability were assessed, and policosanol consistently was found to be equal to or better than placebo. Furthermore, there have been no serious adverse clinical or biochemical effects reported in published studies. Withdrawal rates from policosanol therapy have been the same as placebo.
A postmarketing surveillance study of 27,879 patients from the six major Cuban medical centers supports the findings obtained in randomized, controlled trials.23 A total of 17,225 patients were followed for two years and 10,654 for four years. Most patients received policosanol 5 mg/d. The duration of therapy ranged from one month to four years, with a mean of 2.7 years. During the study only 0.31% (86 participants) reported adverse effects felt to be related to the drug, and only 0.08% (22 participants) discontinued treatment because of adverse effects. The most frequently reported side effects were (incidence): weight loss (0.08%), polyuria (0.07%), polyphagia (0.05%), insomnia (0.05%), headache (0.03%), and dizziness (0.02%).
In another postmarketing surveillance study of 6,611 patients, which included an age-matched control group, a similar side effect profile was reported: weight loss (1.75%), polyuria (0.68%), headache (0.61%), dizziness (0.44%), and polyphagia (0.36%).24 There was no significant difference between the groups in the frequency of any side effect. Over a mean follow-up of 3.1 years, 10.3% of the control group required hospitalization for any cause compared with 7.5% of the policosanol group. All vascular events and death were less frequent in the policosanol group, although this was not a randomized trial.
Policosanol appears to have potent cholesterol-lowering properties, comparable to the effects of various statins. It appears to have few side effects, and a therapeutic effect over a range of doses, permitting its use either alone or in combination with other agents. Also of note, it is much less expensive than the statin drugs ($1.71 per dose vs. $4.51 per dose, average wholesale price). However, a lingering concern is that a single group with a commercial interest in the product has performed all of the published studies. Their findings are therefore open to question until corroborated by other independent research groups, with study participants drawn from other ethnic populations. If the encouraging findings to date are borne out, policosanol has great promise as an addition to the lipid-lowering armamentarium.
What advice should the clinician offer his or her patients about the use of policosanol? First, clinicians must recognize that because it is inexpensive and readily available over the counter, policosanol already is being used by some patients in need of lipid-lowering therapy.
As with most herbs and supplements, a key piece of advice should be, "Know what you are taking." The scientific evidence for the benefit of policosanol is based on the sugar cane-derived version. Although the beeswax version may work as well, when presented with both, the well-tested form is probably the better choice.
Consider all options, including use of policosanol in combination with other lipid-lowering therapies. Statins have the most evidence for reducing the risk of death from CHD, yet when used alone, they often do not lower cholesterol to target levels. This may be especially important in patients who cannot tolerate or afford a treatment regimen including additional prescription medications. However, one caveat is that there are no published studies on the statin-policosanol combination, so we do not know how much more effective it is than either agent used alone.
Continue to follow the literature: As interest in policosanol increases in the United States and elsewhere, additional studies will be published. If the opportunity exists, recommend that patients wanting to use policosanol participate in some of these trials.
Dr. Sasser is Director, Research Epidemiology, R. Stuart Dickson Institute for Health Studies, Carolinas HealthCare System; Dr. Barringer is Assistant Clinical Professor, School of Medicine, University of North Carolina, and Director of Research, Department of Family Medicine, Carolinas HealthCare System, Charlotte, NC.
1. Benner JS, et al. Long-term persistence in use of statin therapy in elderly patients. JAMA 2002;288: 455-461.
2. Policosanol Product Monograph. Dalmer Laboratory. Havana, Cuba.
3. Castano G, et al. Effects of policosanol and pravastatin on lipid profile, platelet aggregation and endothelemia in older hypercholesterolemic patients. Int J Clin Pharm Res 1999;19:105-116.
4. Castano G, et al. Effects of policosanol in hypertensive patients with type II hypercholesterolemia. Curr Ther Res 1996;57:691-699.
5. Menendez R, et al. Policosanol inhibits cholesterol biosynthesis and enhances low density lipoprotein processing in cultured human fibroblasts. Biol Res 1994; 27:199-203.
6. Menendez R, et al. Effect of policosanol on the hepatic cholesterol biosynthesis of normocholesterolemic rats. Biol Res 1996;29:253-257.
7. Menendez R, et al. Cholesterol-lowering effect of policosanol on rabbits with hypercholesterolaemia induced by a wheat starch-casein diet. Br J Nutr 1997;77: 923-932.
8. Pons P, et al. Effects of successive dose increases of policosanol on the lipid profile of patients with type II hypercholesterolaemia and tolerability to treatment. Int J Clin Pharmacol Res 1994;14:27-33.
9. Aneiros E, et al. Effect of successive dose increases of policosanol on the lipid profile and tolerability of treatment. Curr Ther Res 1993;54:304-312.
10. Castano G, et al. Effects of policosanol 20 versus 40 mg/day in the treatment of patients with type II hypercholesterolemia: A 6-month double-blind study. Int J Clin Pharmacol Res 2001;21:43-57.
11. Castano G, et al. A long-term open label study of the efficacy and tolerability of policosanol in patients with high global coronary risk. Curr Ther Res 1999; 60:379-391.
12. Crespo N, et al. Comparative study of the efficacy and tolerability of policosanol and lovastatin in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus. Int J Clin Pharmacol Res 1999;19:117-127.
13. Ortensi G, et al. A comparative study of policosanol versus simvastatin in elderly patients with hypercholesterolemia. Curr Ther Res 1997;58:390-401.
14. Benitez M, et al. A comparative study of policosanol versus pravastatin in patients with type II hypercholesterolemia. Curr Ther Res 1997;58:859-867.
15. Marcello S, et al. Effects of bezafibrate plus policosanol or placebo in patients with combined dyslipidemia: A pilot study. Curr Ther Res 2000;61:346-357.
16. Torres O, et al. Treatment of hypercholesterolemia in NIDDM with policosanol. Diabetes Care 1995;18: 393-397.
17. Crespo N, et al. Effect of policosanol on patients with non-insulin dependent diabetes mellitus and hyper-cholesterolemia: A pilot study. Curr Ther Res 1997;58:44-51.
18. Castano G, et al. Effects of policosanol on older patients with hypertension and type II hypercholesterolaemia. Drugs R D 2002;3:159-172.
19. Pons P, et al. Effects of policosanol in elderly hypercholesterolemic patients. Curr Ther Res 1993;53:265-269.
20. Zardoya R, et al. Effects of policosanol on hypercholesterolemic patients with abnormal serum biochemical indicators of hepatic function. Curr Ther Res 1996;57: 568-577.
21. Davalos JM, et al. Effect of policosanol in hypercholesterolemia due to nephrotic syndrome. X Latinoamerican Congress of Nephrology and Hypertension, 1-4 September, Santiago de Chile, Chile (as reported in Reference 1).
22. Gouni-Berthold I, Berthold HK. Policosanol: Clinical pharmacology and therapeutic significance of a new lipid-lowering agent. Am Heart J 2002;143:356-365.
23. Fernandez L, et al. Policosanol: Results of a postmarketing surveillance study of 27,879 patients. Curr Ther Res 1998;59:717-722.
24. Mas R, et al. Pharmacoepidemiologic study of policosanol. Curr Ther Res 1999;60:458-467.